Detrimental effects of duplicate reads and low complexity regions on RNA- and ChIP-seq data

Background Adapter trimming and removal of duplicate reads are common practices in next-generation sequencing pipelines. Sequencing reads ambiguously mapped to repetitive and low complexity regions can also be problematic for accurate assessment of the biological signal, yet their impact on sequencing data has not received much attention. We investigate how trimming the adapters, removing duplicates, and filtering out reads overlapping low complexity regions influence the significance of biological signal in RNA- and ChIP-seq experiments. Methods We assessed the effect of data processing steps on the alignment statistics and the functional enrichment analysis results of RNA- and ChIP-seq data. We compared differentially processed RNA-seq data with matching microarray data on the same patient samples to determine whether changes in pre-processing improved correlation between the two. We have developed a simple tool to remove low complexity regions, RepeatSoaker, available at https://github.com/mdozmorov/RepeatSoaker, and tested its effect on the alignment statistics and the results of the enrichment analyses. Results Both adapter trimming and duplicate removal moderately improved the strength of biological signals in RNA-seq and ChIP-seq data. Aggressive filtering of reads overlapping with low complexity regions, as defined by RepeatMasker, further improved the strength of biological signals, and the correlation between RNA-seq and microarray gene expression data. Conclusions Adapter trimming and duplicates removal, coupled with filtering out reads overlapping low complexity regions, is shown to increase the quality and reliability of detecting biological signals in RNA-seq and ChIP-seq data

Clinical failures of endovascular abdominal aortic aneurysm repair: Incidence, causes, and management

AbstractObjective: Despite well-documented good early results and benefits of endoluminal stent graft repair of abdominal aortic aneurysm (J Vasc Surg 2002;35:1137-44.)(AAA), the long-term outcome of this method of treatment remains uncertain. In particular, concern exists that late effectiveness and durability are inferior to that of open repair. To determine the incidence and causes of clinical failures of endovascular AAA repair, a 7-year experience with 362 primary AAA endografts was reviewed. Methods: Clinical failures were defined as deaths within 30 days of the procedure, conversions (early and late) to open AAA repair, AAA rupture after endoluminal treatment, or AAA sac growth of more than 5 mm in maximal diameter despite endograft repair. Endoleak status per se was not considered unless it resulted in an adverse event. If clinical problems arose but could be corrected with catheter-based therapies or limited surgical procedures, thereby maintaining the integrity of successful stent graft treatment of the AAA, such cases were considered as primary assisted success and not classified as clinical failures. Results: The average follow-up period was 1.5 years. Six deaths (1.6%) occurred after the procedure, all in elderly patients or patients at high risk. Five patients (1.4%) needed early conversion (immediate, 2 days) to open repair for access problems or technical difficulties with deployment, resulting in an implantation success rate of 98.6%. Eight patients (2.2%) underwent late conversion for a variety of problems, including AAA expansion (n = 4), endograft thrombosis (n = 1), secondary graft infection (n = 2), and rupture at 3 years (n = 1). Rupture occurred in an additional two patients for a total incidence rate of 0.8%. AAA sac growth of greater than 5 mm was observed in 20 patients (5.6%), four of whom have undergone successful catheter-based treatments to date. Overall, 39 patients (10.7%) needed catheter-based (n = 45) or limited surgical (n = 4) reinterventions for a variety of late problems that were successful in 92%. Conclusion: In our 7-year experience, one or more clinical failures of endovascular AAA repair were observed in 31 patients (8.3%). Reinterventions were necessitated in a total of 10.7% of patients but were usually successful in maintaining AAA exclusion and limiting AAA growth. These results emphasize that endovascular repair provides good results and many benefits for most properly selected patients but is not as durable as standard open repair. (J Vasc Surg 2002;35:1137-44.

Metrics of progress in the understanding and management of threats to Australian birds

Although evidence‐based approaches have become commonplace for determining the success of conservation measures for the management of threatened taxa, there are no standard metrics for assessing progress in research or management. We developed 5 metrics to meet this need for threatened taxa and to quantify the need for further action and effective alleviation of threats. These metrics (research need, research achievement, management need, management achievement, and percent threat reduction) can be aggregated to examine trends for an individual taxon or for threats across multiple taxa. We tested the utility of these metrics by applying them to Australian threatened birds, which appears to be the first time that progress in research and management of threats has been assessed for all threatened taxa in a faunal group at a continental scale. Some research has been conducted on nearly three‐quarters of known threats to taxa, and there is a clear understanding of how to alleviate nearly half of the threats with the highest impact. Some management has been attempted on nearly half the threats. Management outcomes ranged from successful trials to complete mitigation of the threat, including for one‐third of high‐impact threats. Progress in both research and management tended to be greater for taxa that were monitored or occurred on oceanic islands. Predation by cats had the highest potential threat score. However, there has been some success reducing the impact of cat predation, so climate change (particularly drought), now poses the greatest threat to Australian threatened birds. Our results demonstrate the potential for the proposed metrics to encapsulate the major trends in research and management of both threats and threatened taxa and provide a basis for international comparisons of evidence‐based conservation science

The low-order wavefront sensor for the PICTURE-C mission

The PICTURE-C mission will fly a 60 cm off-axis unobscured telescope and two high-contrast coronagraphs in successive high-altitude balloon flights with the goal of directly imaging and spectrally characterizing visible scattered light from exozodiacal dust in the interior 1-10 AU of nearby exoplanetary systems. The first flight in 2017 will use a 10^(-4) visible nulling coronagraph (previously flown on the PICTURE sounding rocket) and the second flight in 2019 will use a 10^(-7) vector vortex coronagraph. A low-order wavefront corrector (LOWC) will be used in both flights to remove time-varying aberrations from the coronagraph wavefront. The LOWC actuator is a 76-channel high-stroke deformable mirror packaged on top of a tip-tilt stage. This paper will detail the selection of a complementary high-speed, low-order wavefront sensor (LOWFS) for the mission. The relative performance and feasibility of several LOWFS designs will be compared including the Shack-Hartmann, Lyot LOWFS, and the curvature sensor. To test the different sensors, a model of the time-varying wavefront is constructed using measured pointing data and inertial dynamics models to simulate optical alignment perturbations and surface deformation in the balloon environment

The EDGE-CALIFA survey: validating stellar dynamical mass models with CO kinematics

Deriving circular velocities of galaxies from stellar kinematics can provide an estimate of their total dynamical mass, provided a contribution from the velocity dispersion of the stars is taken into account. Molecular gas (e.g., CO) on the other hand, is a dynamically cold tracer and hence acts as an independent circular velocity estimate without needing such a correction. In this paper we test the underlying assumptions of three commonly used dynamical models, deriving circular velocities from stellar kinematics of 54 galaxies (S0-Sd) that have observations of both stellar kinematics from the CALIFA survey, and CO kinematics from the EDGE survey. We test the Asymmetric Drift Correction (ADC) method, as well as Jeans, and Schwarzschild models. The three methods each reproduce the CO circular velocity at 1Re to within 10%. All three methods show larger scatter (up to 20%) in the inner regions (R < 0.4Re) which may be due to an increasingly spherical mass distribution (which is not captured by the thin disk assumption in ADC), or non-constant stellar M/L ratios (for both the JAM and Schwarzschild models). This homogeneous analysis of stellar and gaseous kinematics validates that all three models can recover Mdyn at 1Re to better than 20%, but users should be mindful of scatter in the inner regions where some assumptions may break down.Comment: 22 pages, 18 figures, Accepted for publication in MNRA

Effects of bardoxolone methyl on body weight, waist circumference and glycemic control in obese patients with type 2 diabetes mellitus and stage 4 chronic kidney disease

AimsObesity is associated with progression of chronic kidney disease (CKD). Treatment with bardoxolone methyl in a multinational phase 3 trial, Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes (BEACON), resulted in increases in estimated glomerular filtration rate (eGFR) with concurrent reductions in body weight. We performed post-hoc analyses to further characterize reductions in body weight with bardoxolone methyl.MethodsEligible patients with type 2 diabetes (T2DM) and CKD stage 4 (eGFR 15 to &lt;30 mL/min/1.73 m2) were randomized 1:1 to receive once-daily oral dose of bardoxolone methyl (20 mg) or placebo.ResultsBEACON enrolled 2185 patients. Patients randomized to bardoxolone methyl experienced significant reductions in body weight from baseline relative to patients randomized to placebo (-5.7 kg; 95% CI: -6.0 to -5.3 kg; p &lt; 0.001). In patients randomized to bardoxolone methyl, rate and magnitude of body weight loss were proportional to baseline BMI. Bardoxolone methyl resulted in significant reductions in waist circumference and improved glycemic control.ConclusionsBardoxolone methyl resulted in significant weight loss in a generally obese patient population with T2DM and stage 4 CKD, with the magnitude and rate dependent on baseline BMI

Neoadjuvant chemotherapy versus debulking surgery in advanced tubo-ovarian cancers: pooled analysis of individual patient data from the EORTC 55971 and CHORUS trials

Background: Individual patient data from two randomised trials comparing neoadjuvant chemotherapy with upfront debulking surgery in advanced tubo-ovarian cancer were analysed to examine long-term outcomes for patients and to identify any preferable therapeutic approaches for subgroup populations. Methods: We did a per-protocol pooled analysis of individual patient data from the European Organisation for Research and Treatment of Cancer (EORTC) 55971 trial (NCT00003636) and the Medical Research Council Chemotherapy Or Upfront Surgery (CHORUS) trial (ISRCTN74802813). In the EORTC trial, eligible women had biopsy-proven International Federation of Gynecology and Obstetrics (FIGO) stage IIIC or IV invasive epithelial tubo-ovarian carcinoma. In the CHORUS trial, inclusion criteria were similar to those of the EORTC trial, and women with apparent FIGO stage IIIA and IIIB disease were also eligible. The main aim of the pooled analysis was to show non-inferiority in overall survival with neoadjuvant chemotherapy compared with upfront debulking surgery, using the reverse Kaplan-Meier method. Tests for heterogeneity were based on Cochran's Q heterogeneity statistic. Findings: Data for 1220 women were included in the pooled analysis, 670 from the EORTC trial and 550 from the CHORUS trial. 612 women were randomly allocated to receive upfront debulking surgery and 608 to receive neoadjuvant chemotherapy. Median follow-up was 7·6 years (IQR 6·0–9·6; EORTC, 9·2 years [IQR 7·3–10·4]; CHORUS, 5·9 years [IQR 4·3–7·4]). Median age was 63 years (IQR 56–71) and median size of the largest metastatic tumour at diagnosis was 8 cm (IQR 4·8–13·0). 55 (5%) women had FIGO stage II–IIIB disease, 831 (68%) had stage IIIC disease, and 230 (19%) had stage IV disease, with staging data missing for 104 (9%) women. In the entire population, no difference in median overall survival was noted between patients who underwent neoadjuvant chemotherapy and upfront debulking surgery (27·6 months [IQR 14·1–51·3] and 26·9 months [12·7–50·1], respectively; hazard ratio [HR] 0·97, 95% CI 0·86–1·09; p=0·586). Median overall survival for EORTC and CHORUS patients was significantly different at 30·2 months (IQR 15·7–53·7) and 23·6 months (10·5–46·9), respectively (HR 1·20, 95% CI 1·06–1·36; p=0·004), but was not heterogeneous (Cochran's Q, p=0·17). Women with stage IV disease had significantly better outcomes with neoadjuvant chemotherapy compared with upfront debulking surgery (median overall survival 24·3 months [IQR 14·1–47·6] and 21·2 months [10·0–36·4], respectively; HR 0·76, 95% CI 0·58–1·00; p=0·048; median progression-free survival 10·6 months [7·9–15·0] and 9·7 months [5·2–13·2], respectively; HR 0·77, 95% CI 0·59–1·00; p=0·049). Interpretation: Long-term follow-up data substantiate previous results showing that neoadjuvant chemotherapy and upfront debulking surgery result in similar overall survival in advanced tubo-ovarian cancer, with better survival in women with stage IV disease with neoadjuvant chemotherapy. This pooled analysis, with long-term follow-up, shows that neoadjuvant chemotherapy is a valuable treatment option for patients with stage IIIC–IV tubo-ovarian cancer, particularly in patients with a high tumour burden at presentation or poor performance status

Developing an intervention to facilitate family communication about inherited genetic conditions, and training genetic counsellors in its delivery.

Many families experience difficulty in talking about an inherited genetic condition that affects one or more of them. There have now been a number of studies identifying the issues in detail, however few have developed interventions to assist families. The SPRinG collaborative have used the UK Medical Research Council's guidance on Developing and Evaluating Complex Interventions, to work with families and genetic counsellors (GCs) to co-design a psycho-educational intervention to facilitate family communication and promote better coping and adaptation to living with an inherited genetic condition for parents and their children (<18 years). The intervention is modelled on multi-family discussion groups (MFDGs) used in psychiatric settings. The MFDG was developed and tested over three phases. First focus groups with parents, young people, children and health professionals discussed whether MFDG was acceptable and proposed a suitable design. Using evidence and focus group data, the intervention and a training manual were developed and three GCs were trained in its delivery. Finally, a prototype MFDG was led by a family therapist and co-facilitated by the three GCs. Data analysis showed that families attending the focus groups and intervention thought MFDG highly beneficial, and the pilot sessions had a significant impact on their family' functioning. We also demonstrated that it is possible to train GCs to deliver the MFDG intervention. Further studies are now required to test the feasibility of undertaking a definitive randomised controlled trial to evaluate its effectiveness in improving family outcomes before implementing into genetic counselling practice.The National Institute of Health Research funded the study but any views expressed do not necessarily reflect those of the Authority. Funded by NIHR reference number: RP-DG-1211-10015

Limits to Rest-Frame Ultraviolet Emission From Far-Infrared-Luminous z~6 Quasar Hosts

We report on a Hubble Space Telescope search for rest-frame ultraviolet emission from the host galaxies of five far-infrared-luminous $z\simeq{}6$ quasars and the $z=5.85$ hot-dust free quasar SDSS J0005-0006. We perform 2D surface brightness modeling for each quasar using a Markov-Chain Monte-Carlo estimator, to simultaneously fit and subtract the quasar point source in order to constrain the underlying host galaxy emission. We measure upper limits for the quasar host galaxies of $m_J>22.7$ mag and $m_H>22.4$ mag, corresponding to stellar masses of $M_\ast<2\times10^{11}M_\odot$. These stellar mass limits are consistent with the local $M_{\textrm{BH}}$-$M_\ast$ relation. Our flux limits are consistent with those predicted for the UV stellar populations of $z\simeq6$ host galaxies, but likely in the presence of significant dust ($\langle A_{\mathrm{UV}}\rangle\simeq 2.6$ mag). We also detect a total of up to 9 potential $z\simeq6$ quasar companion galaxies surrounding five of the six quasars, separated from the quasars by 1.4''-3.2'', or 8.4-19.4 kpc, which may be interacting with the quasar hosts. These nearby companion galaxies have UV absolute magnitudes of -22.1 to -19.9 mag, and UV spectral slopes $\beta$ of -2.0 to -0.2, consistent with luminous star-forming galaxies at $z\simeq6$. These results suggest that the quasars are in dense environments typical of luminous $z\simeq6$ galaxies. However, we cannot rule out the possibility that some of these companions are foreground interlopers. Infrared observations with the James Webb Space Telescope will be needed to detect the $z\simeq6$ quasar host galaxies and better constrain their stellar mass and dust content.Comment: 22 pages, 13 figures. Accepted for publication in Ap